📚 Article Archive

Hypoxia studies in non‑small cell lung cancer: Pathogenesis and clinical implications (Review)

H Zhou, J Ferlay, RL Siegel +660 more · 2025 · Oncology Reports · added 2026-04-20

H Zhou, J Ferlay, RL Siegel, M Laversanne, I Soerjomataram, A Jemal, F Bray, PS Steeg, KD Miller, HE Fuchs, FX Xu, YL Zhang, JJ Liu, DD Zhang, HB Chen, K Saxena, MK Jolly, JA Bertout, SA Patel, MC Simon, X Meng, FM Kong, J Yu, A Challapalli, L Carroll, EO Aboagye, DC Hinshaw, LA Shevde, P Desai, N Takahashi, R Kumar, S Nichols, J Malin, A Hunt, C Schultz, Y Cao, D Tillo, D Nousome, FF Tam, KL Ning, M Lee, JM Dumlao, JC Choy, AA Tirpe, D Gulei, SM Ciortea, C Crivii, I Berindan-Neagoe, EB Rankin, AJ Giaccia, GN Masoud, W Li, Y Della Rocca, L Fonticoli, TS Rajan, O Trubiani, S Caputi, F Diomede, J Pizzicannella, GD Marconi, SG Zeng, X Lin, JC Liu, J Zhou, RY Hapke, SM Haake, S Musleh Ud Din, SG Streit, BT Huynh, C Hana, AN Abraham, A Hussein, S Liu, Y Zhan, J Luo, J Feng, J Lu, H Zheng, Q Wen, S Fan, C Wang, S Xu, X Yang, W Luo, H Hu, R Chang, J Zhong, M Knabel, R O'Meally, RN Cole, A Pandey, GL Semenza, Y Wei, D Wang, F Jin, Z Bian, L Li, H Liang, M Li, L Shi, C Pan, D Zhu, X Ji, R Zhu, C Gao, H Xie, X Gong, H Jiang, H Zhao, M Zhang, Y He, X Li, Y Xu, X Liu, S Jiang, R Wang, H Yan, L Jin, X Dou, D Chen, V Becker, X Yuan, AS Boewe, E Ampofo, E Ebert, J Hohneck, RM Bohle, E Meese, Y Zhao, MD Menger, J Zhao, CR Qiao, Z Ding, YL Sheng, XN Li, Y Yang, DY Zhu, CY Zhang, DL Liu, K Wu, S Zhao, C Han, Y Zhang, F Liu, J Ren, HL Yin, HW Xu, QY Lin, RD Leone, JD Powell, Z Yu, J Zou, F Xu, J Jin, G Yu, J Gu, S Yang, X Wang, Y Wu, J Wei, J Xu, AL Jackson, B Zhou, WY Kim, KL Eales, KER Hollinshead, DA Tennant, E Dai, W Wang, Y Li, D Ye, R Courtnay, DC Ngo, N Malik, K Ververis, SM Tortorella, TC Karagiannis, F Luo, N Yan, S Li, G Cao, Q Cheng, Q Xia, H Wang, S Shang, MZ Wang, Z Xing, N He, H Nisar, PM Sanchidrián González, M Brauny, FM Labonté, C Schmitz, MD Roggan, B Konda, CE Hellweg, Z Guo, L Hu, Q Wang, Y Wang, XP Liu, C Chen, W Hu, X Zhang, C Liang, C Wu, S Wan, L Xu, S Wang, J Wang, X Huang, C Zhang, L Zhou, Y Du, C Li, H Ren, L Zheng, PE Porporato, N Filigheddu, JMB Pedro, G Kroemer, L Galluzzi, OT Brustugun, RX Huang, PK Zhou, H Chen, Z Han, Q Luo, Q Li, H Zuo, L Gong, C Liu, S Han, T Zhou, LY Zhang, JZ He, ZM Miao, YY Li, YM Zhang, ZW Liu, SZ Zhang, Y Chen, GC Zhou, YQ Liu, LH Gray, AD Conger, M Ebert, S Hornsey, OC Scott, AB Herrera-Campos, E Zamudio-Martinez, D Delgado-Bellido, M Fernández-Cortés, LM Montuenga, FJ Oliver, A Garcia-Diaz, Q Guo, F Lan, X Yan, Z Xiao, Q Zhang, S Roy, S Kumaravel, A Sharma, CL Duran, KJ Bayless, S Chakraborty, CY Hu, CF Hung, PC Chen, JY Hsu, CT Wang, MD Lai, YS Tsai, AL Shiau, GS Shieh, CL Wu, A Mancino, T Schioppa, P Larghi, F Pasqualini, M Nebuloni, IH Chen, S Sozzani, JM Austyn, A Mantovani, A Sica, X Peng, J Huang, Y Tao, HK Eltzschig, LF Thompson, J Karhausen, RJ Cotta, JC Ibla, SC Robson, SP Colgan, J Li, L Wang, X Chen, Y Ping, L Huang, D Yue, Z Zhang, F Wang, SM An, HM Lei, XP Ding, F Sun, YB Tang, HZ Chen, Y Shen, L Zhu, A Kogita, Y Togashi, H Hayashi, S Sogabe, M Terashima, MA De Velasco, K Sakai, Y Fujita, S Tomida, Y Takeyama, S Karan, MY Cho, H Lee, HS Park, M Sundararajan, JL Sessler, KS Hong, MHY Cheng, Y Mo, G Zheng, LC Clark, R Wolf, D Granger, Z Taylor, X Sun, G Niu, N Chan, B Shen, MV Shirmanova, MM Lukina, MA Sirotkina, LE Shimolina, VV Dudenkova, NI Ignatova, S Tobita, VI Shcheslavskiy, EV Zagaynova, JM Vanderkooi, G Maniara, TJ Green, DF Wilson, CJ Koch, SM Evans, MR Horsman, BS Sørensen, M Busk, DW Siemann, C Huang, J Liang, X Lei, X Xu, L Luo, X Hu, J Gou, W Lin, F Yang, C Liao, D Nasri, R Manwar, A Kaushik, EE Er, K Avanaki, KA Krohn, JM Link, RP Mason, JR Brender, Y Saida, N Devasahayam, MC Krishna, S Kishimoto, I Godet, S Doctorman, F Wu, DM Gilkes, K Matsumoto, JB Mitchell, W Qin, C Xu, C Yu, S Shen, W Huang, DS Vikram, JL Zweier, P Kuppusamy, B Epel, MK Bowman, C Mailer, HJ Halpern, B Hao, H Dong, R Xiong, C Song, N Li, Q Geng, R Zhang, L Lai, J He, D You, W Duan, X Dong, Y Zhu, L Lin, C Ostheimer, M Bache, A Güttler, M Kotzsch, D Vordermark, A Giatromanolaki, AL Harris, AH Banham, CA Contrafouris, MI Koukourakis, H Geng, L Chen, S Lv, SJ Kim, ZN Rabbani, RT Vollmer, EG Schreiber, E Oosterwijk, MW Dewhirst, Z Vujaskovic, MJ Kelley, D Coppola, M Szabo, D Boulware, P Muraca, M Alsarraj, AF Chambers, TJ Yeatman, T Reese, K Stępień, RP Ostrowski, E Matyja, SW Kim, IK Kim, JH Ha, CD Yeo, HH Kang, JW Kim, SH Lee, O Thews, P Vaupel, M Heyboer, D Sharma, W Santiago, N McCulloch, LW Jones, BL Viglianti, JA Tashjian, SM Kothadia, ST Keir, SJ Freedland, MQ Potter, EJ Moon, T Schroeder, JE Herndon, S Jo, J Jeon, G Park, HK Do, J Kang, KJ Ahn, SY Ma, YM Choi, D Kim, B Youn, Y Ki, P Ghosh, C Vidal, S Dey, L Zhang, TM Ashton, WG McKenna, LA Kunz-Schughart, GS Higgins, B Kalyanaraman, G Cheng, M Hardy, M You, M Shameem, AJ Bagherpoor, A Nakhi, P Dosa, G Georg, F Kassie, M Skwarski, DR McGowan, E Belcher, F Di Chiara, D Stavroulias, M McCole, JL Derham, KY Chu, E Teoh, J Chauhan, M Benej, X Hong, S Vibhute, S Scott, J Wu, E Graves, QT Le, AC Koong, B Yu, S Sohoni, T Wang, SP Kalainayakan, PC Konduri, A Ashrafi, P Modareszadeh, N Salamat, PS Alemi, E Berisha, TW Secomb, V Sukhatme, G Bouche, L Meheus, VP Sukhatme, P Pantziarka, BJT Reymen, MW van Gisbergen, AJG Even, CML Zegers, M Das, E Vegt, JE Wildberger, FM Mottaghy, A Yaromina, LJ Dubois, PP Wong, N Bodrug, KM Hodivala-Dilke, S Guelfi, K Hodivala-Dilke, G Bergers, C Wigerup, S Påhlman, D Bexell, Y Xia, HK Choi, K Lee, L Iommarini, AM Porcelli, G Gasparre, I Kurelac, N Albadari, S Deng, J Ma, K Cao, X Ling, P Zhang, J Zhu, H Deng, P Li, Q Hang, Y Jin, M Chen, MS Lara, CM Blakely, JW Riess, H Zhu, S Zhang, W Tian, C Cao, L Shu, A Mahdi, B Darvishi, K Majidzadeh-A, M Salehi, L Farahmand, Z Xie, T Zou, JL Bryant, SL Meredith, KJ Williams, A White, WR Wilson, MP Hay, SX Chen, J Zhang, F Xue, W Liu, Y Kuang, B Gu, S Song, F Shepherd, G Koschel, J Von Pawel, U Gatzmeier, N Van Zandwiyk, P Woll, R Van Klavren, P Krasko, P Desimone, M Nicolson, L Marcu, I Olver, K Graham, E Unger, D Lindsay, CM Garvey, SM Mumenthaler, J Foo, C Meaney, GG Powathil, P Lambin, M Kohandel, BT Oronsky, SJ Knox, JJ Scicinski, B Oronsky, J Scicinski, S Ning, D Peehl, A Oronsky, P Cabrales, M Bednarski, S Knox, L Zhao, C Shen, Y Luo, X Hou, Y Qi, Z Huang, L Gao, M Wu, Y Zhou, X Feng, Z Wu, X Rao, R Zhou, R Meng, P Dey, R Das, S Chatterjee, R Paul, U Ghosh, Y Demizu, O Fujii, H Iwata, N Fuwa, SM Bentzen, V Gregoire, G Meijer, J Steenhuijsen, M Bal, K De Jaeger, D Schuring, J Theuws Show less

Non-small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite sig Show more

Non-small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite significant advances in targeted therapy and immunotherapy, the overall prognosis of patients with NSCLC remains poor. Hypoxia is a critical driving factor in tumor progression, influencing the biological behavior of tumor cells through complex molecular mechanisms. The present review systematically examined the role of the hypoxic microenvironment in NSCLC, demonstrating its crucial role in promoting tumor cell growth, invasion and metastasis. Additionally, it has been previously reported that the hypoxic microenvironment enhances tumor cell resistance by activating hypoxia-inducible factor and regulating exosome secretion. The hypoxic microenvironment also enables tumor cells to adapt to low oxygen and nutrient-deficient conditions by enhancing metabolic reprogramming, such as through upregulating glycolysis. Further studies have shown that the hypoxic microenvironment facilitates immune escape by modulating tumor-associated immune cells and suppressing the antitumor response of the immune system. Moreover, the hypoxic microenvironment increases tumor resistance to radiotherapy, chemotherapy and other types of targeted therapy through various pathways, significantly reducing the therapeutic efficacy of these treatments. Therefore, it could be suggested that early detection of cellular hypoxia and targeted therapy based on hypoxia may offer new therapeutic approaches for patients with NSCLC. The present review not only deepened the current understanding of the mechanisms of action and role of the hypoxic microenvironment in NSCLC but also provided a solid theoretical basis for the future development of precision treatments for patients with NSCLC. Show less

📄 PDF DOI: 10.3892/or.2024.8862

anticancer review

Ovarian cancer cells regulate their mitochondrial content and high mitochondrial content is associated with a poor prognosis

S Weigelt, RA Weinberg, S Mei +175 more · 2024 · BMC Cancer · BioMed Central · added 2026-04-20

S Weigelt, RA Weinberg, S Mei, X Chen, K Wang, Y Chen, N Colombo, C Sessa, A du Bois, J Ledermann, WG McCluggage, I McNeish, H Abdel Mageed, K Van Der Speeten, P Sugarbaker, N Ahmed, R Escalona, D Leung, E Chan, G Kannourakis, W Chowanadisai, SM Messerli, DH Miller, JE Medina, JW Hamilton, MA Messerli, AM Haslehurst, M Koti, M Dharsee, P Nuin, K Evans, J Geraci, P Ghosh, C Vidal, S Dey, L Zhang, LF Dong, J Neuzil, HD Osiewacz, M Huang, CR Myers, Y Wang, M You, SE Weinberg, NS Chandel, O WARBURG, DC Wallace, RM Pascale, DF Calvisi, MM Simile, CF Feo, F Feo, G Kroemer, L Galluzzi, C Brenner, N Joza, E Tasdemir, MC Maiuri, M Hengartner, JM Abrams, Y Ding, V Labitzky, K Legler, M Qi, U Schumacher, B Schmalfeldt, L Oliveira-Ferrer, J Dietl, C Bartmann, C Stürken, J Ghulam, C Stuerken, D Wicklein, R Pries, B Wollenberg, M Metzen, M Bruns, W Deppert, N Lüders, E Adam, DJ Flavell, D Boehm, SA Brooks, AJ Leathem, E Hjerpe, S Egyhazi, J Carlson, MF Stolt, K Schedvins, H Johansson, J Guo, X Li, W Zhang, S Zhu, L Chen, S Fulda, L Bockelmann, C Starzonek, AC Niehoff, U Karst, J Thomale, H Schluter, LC Bockelmann, WX Zong, JD Rabinowitz, E White, R Moreno-Sánchez, S Rodríguez-Enríquez, A Marín-Hernández, E Saavedra, Y Kubo, K Tanaka, Y Masuike, T Takahashi, K Yamashita, T Makino, CT Hensley, B Faubert, Q Yuan, N Lev-Cohain, E Jin, J Kim, LA Moukarzel, L Ferrando, H Dopeso, A Stylianou, T Basili, F Pareja, RJ DeBerardinis, JJ Lum, G Hatzivassiliou, CB Thompson, S Dar, J Chhina, I Mert, D Chitale, T Buekers, H Kaur, VW Liu, WC Xue, AN Cheung, HY Ngan, HY Lim, QS Ho, J Low, M Choolani, KP Wong, F Vazquez, JH Lim, H Chim, K Bhalla, G Girnun, K Pierce, EM Kuntz, P Baquero, AM Michie, K Dunn, S Tardito, TL Holyoake, DR Hodge, EM Hurt, WL Farrar, DS Matassa, MR Amoroso, H Lu, R Avolio, D Arzeni, C Procaccini, M Peiris-Pagès, UE Martinez-Outschoorn, RG Pestell, F Sotgia, MP Lisanti, AS Anderson, PC Roberts, MI Frisard, MW Hulver, EM Schmelz Show less

Most cancer patients ultimately die from the consequences of distant metastases. As metastasis formation consumes energy mitochondria play an important role during this process as they are the most im Show more

Most cancer patients ultimately die from the consequences of distant metastases. As metastasis formation consumes energy mitochondria play an important role during this process as they are the most important cellular organelle to synthesise the energy rich substrate ATP, which provides the necessary energy to enable distant metastasis formation. However, mitochondria are also important for the execution of apoptosis, a process which limits metastasis formation. We therefore wanted to investigate the mitochondrial content in ovarian cancer cells and link its presence to the patient’s prognosis in order to analyse which of the two opposing functions of mitochondria dominates during the malignant progression of ovarian cancer. Monoclonal antibodies directed against different mitochondrial specific proteins, namely heat shock proteins 60 (HSP60), fumarase and succinic dehydrogenase, were used in immunohistochemistry in preliminary experiments to identify the antibody most suited to detect mitochondria in ovarian cancer cells in clinical tissue samples. The clearest staining pattern, which even delineated individual mitochondria, was seen with the anti-HSP60 antibody, which was used for the subsequent clinical study staining primary ovarian cancers ( n = 155), borderline tumours ( n = 24) and recurrent ovarian cancers ( n = 26). The staining results were semi-quantitatively scored into three groups according to their mitochondrial content: low ( n = 26), intermediate ( n = 50) and high ( n = 84). Survival analysis showed that high mitochondrial content correlated with a statistically significant overall reduced survival rate In addition to the clinical tissue samples, mitochondrial content was analysed in ovarian cancer cells grown in vitro (cell lines: OVCAR8, SKOV3, OVCAR3 and COV644) and in vivo in severe combined immunodeficiency (SCID) mice. In in vivo grown SKOV3 and OVCAR8 cells, the number of mitochondria positive cells was markedly down-regulated compared to the in vitro grown cells indicating that mitochondrial number is subject to regulatory processes. As high mitochondrial content is associated with a poor prognosis, the provision of high energy substrates by the mitochondria seems to be more important for metastasis formation than the inhibition of apoptotic cell death, which is also mediated by mitochondria. In vivo and in vitro grown human ovarian cancer cells showed that the mitochondrial content is highly adaptable to the growth condition of the cancer cells. Show less

📄 PDF DOI: 10.1186/s12885-023-11667-8

mitochondria

Targeting Transcription Factors ATF5, CEBPB and CEBPD with Cell-Penetrating Peptides to Treat Brain and Other Cancers

A.W. Greene, J. Baek, O. Ashenberg +1163 more · 2023 · Cells · MDPI · added 2026-04-20

A.W. Greene, J. Baek, O. Ashenberg, A.E. Keating, W.H. Landschulz, P.F. Johnson, S.L. McKnight, C.R. Vinson, K.C. Garcia, J. Lekstrom-Himes, K.G. Xanthopoulos, P. Agre, T. Hai, S.M. Boyd, J.R. Newman, J. Jumper, R. Evans, A. Pritzel, T. Green, M. Figurnov, O. Ronneberger, K. Tunyasuvunakool, R. Bates, A. Zidek, A. Potapenko, M. Varadi, S. Anyango, M. Deshpande, S. Nair, C. Natassia, G. Yordanova, D. Yuan, O. Stroe, G. Wood, A. Laydon, T.K. Sears, J.M. Angelastro, P. Deng, C.M. Haynes, P. Paerhati, J. Liu, Z. Jin, T. Jakos, S. Zhu, L. Qian, J. Zhu, Y. Yuan, T. Sebastian, J.J. Smink, A. Leutz, S.E. van der Krieken, H.E. Popeijus, R.P. Mensink, J. Plat, M. Pulido-Salgado, J.M. Vidal-Taboada, J. Saura, M. Miller, A.J. Spike, J.M. Rosen, K. Balamurugan, E. Sterneck, L. Klimaschewski, S. Tang, O.V. Vitolo, T.A. Weissman, L.T. Donlin, M.L. Shelanski, L.A. Greene, J.M. Aletta, A. Rukenstein, S.H. Green, T.N. Ignatova, V.G. Kukekov, D.A. Steindler, G.B. Stengren, C. Mendelsohn, J.L. Mason, J.E. Goldman, G. Lin, M. Umemura, T. Ogura, A. Matsuzaki, H. Nakano, K. Takao, T. Miyakawa, Y. Takahashi, Y. Kaneko, R. Tanabe, L.R. Devireddy, J.G. Teodoro, F.A. Richard, M.R. Green, S.P. Persengiev, Z. Sheng, L. Li, L.J. Zhu, T.W. Smith, A. Demers, A.H. Ross, R.P. Moser, P.D. Canoll, J. Kuo, M. Weicker, A. Costa, J.N. Bruce, R. Huang, D. Qian, M. Hu, X. Zhang, J. Song, H. Chen, B. Wang, M. Wang, L. Wei, L. Zhang, D.X. Liu, J. Feldheim, A.F. Kessler, D. Schmitt, L. Wilczek, T. Linsenmann, M. Dahlmann, C.M. Monoranu, R.I. Ernestus, C. Hagemann, M. Lohr, D. York, C.D. Sproul, N. Chikere, P.J. Dickinson, T. Wang, R. Yang, J.L. Huang, G. Jiang, Q.X. Song, X. Gu, X.L. Wang, H.H. Song, L.P. Chen, Y.Y. Lin, D. Jiang, D. Zhou, L.R. Palam, L. Jiang, J. Narasimhan, K.A. Staschke, R.C. Wek, M. Costa-Mattioli, P. Walter, X.M. Hua, J. Wang, D.M. Qian, J.Y. Song, X.L. Zhu, R. Zhou, Y.D. Zhao, X.Z. Zhou, Z. Li, H. Li, H. Xie, M. Fan, N. Zhang, J. Ma, S. Che, H.Y. Lee, S.E. Monaco, M. Szabolcs, S. Dong, C.L. Nutt, R.A. Betensky, A.O. Stemmer-Rachamimov, N.C. Denko, K.L. Ligon, D.H. Rowitch, D.N. Louis, X. Wang, F. Xing, I. Herskowitz, B.N. Nguyen, L.W. Elmore, S.E. Holt, S. Dejager, M. Mietus-Snyder, A. Friera, R.E. Pitas, D. Krylov, M. Olive, C. Vinson, S.C. Williams, C. Dezan, D.R. Echlin, K. Gardner, E. Taparowsky, A. Arias, M.W. Lame, L. Santarelli, R. Hen, M. Assanah, R. Lochhead, A. Ogden, J. Bruce, J. Goldman, P. Canoll, G. Hesselager, L. Uhrbom, B. Westermark, M. Nister, N. Vale, D. Duarte, S. Silva, A.S. Correia, B. Costa, M.J. Gouveia, A. Ferreira, E. Dupont, A. Prochiantz, A. Joliot, C.C. Cates, A.D. Arias, L.S. Nakayama Wong, M. Sidorov, G. Cayanan, D.J. Rowland, J. Fung, G. Karpel-Massler, M.D. Siegelin, N.A. Ciaccio, T.S. Reynolds, C.R. Middaugh, J.S. Laurence, B.A. Horst, C. Shu, L. Chau, T. Tsujiuchi, C.S. Peters, X. Liang, S. Li, S. Kannan, Y. Peng, R. Taub, R.H. Diamond, M.L. Moreno, R.L. Bauer, X. Sun, P. Jefferson, Q. Zhou, T. Nakajima, S. Kinoshita, T. Sasagawa, K. Sasaki, M. Naruto, T. Kishimoto, S. Akira, J. Homma, R. Yamanaka, N. Yajima, N. Tsuchiya, N. Genkai, M. Sano, R. Tanaka, M.S. Carro, W.K. Lim, M.J. Alvarez, R.J. Bollo, X. Zhao, E.Y. Snyder, E.P. Sulman, S.L. Anne, F. Doetsch, H. Colman, L.A. Cooper, D.A. Gutman, C. Chisolm, C. Appin, J. Kong, Y. Rong, T. Kurc, E.G. Van Meir, J.H. Saltz, C.S. Moreno, T. Chu, E.J. Rice, G.T. Booth, H.H. Salamanca, Z. Wang, L.J. Core, S.L. Longo, R.J. Corona, L.S. Chin, J.T. Lis, T. Kudo, M.T. Prentzell, S.R. Mohapatra, F. Sahm, Z. Zhao, I. Grummt, W. Wick, C.A. Opitz, M. Platten, E.W. Green, K. Lei, Y. Xia, X.C. Wang, E.H. Ahn, L. Jin, K. Ye, D. Wang, X. Ruan, X. Liu, Y. Xue, L. Shao, C. Yang, L. Zhu, Y. Yang, B. Yu, S.M. Wang, W.C. Lin, H.Y. Lin, Y.L. Chen, C.Y. Ko, J.M. Wang, J. Halliday, K. Helmy, S.S. Pattwell, K.L. Pitter, Q. LaPlant, T. Ozawa, E.C. Holland, M. Minata, A. Audia, J. Shi, S. Lu, J. Bernstock, M.S. Pavlyukov, A. Das, S.H. Kim, Y.J. Shin, Y. Lee, J. Yin, Y.T. Oh, J.Y. Kim, S.S. Kim, E. Choi, T.H. Kim, J.H. Hong, N. Chang, H.J. Cho, J.K. Sa, D. Aguilar-Morante, M. Cortes-Canteli, M. Sanz-Sancristobal, A. Santos, A. Perez-Castillo, J.A. Morales-Garcia, F. Di Pascale, S. Nama, M. Muhuri, S. Quah, H.M. Ismail, X.H.D. Chan, G.M. Sundaram, R. Ramalingam, B. Burke, P. Sampath, T.I. Hsu, J.Y. Chuang, T.J. Kao, S.W. Lim, W.B. Yang, C.C. Huang, Y.T. Tsai, W.C. Chang, K. Biserova, A. Jakovlevs, R. Uljanovs, I. Strumfa, Y. Gao, B. Liu, L. Feng, B. Sun, S. He, G. Wu, G. E, C. Liu, Z. Gao, J. Xu, Y. Fan, Y. Qi, S. Wang, S. Zhao, X. Guo, H. Xue, L. Deng, R. Zhao, L. Selagea, A. Mishra, M. Anand, J. Ross, C. Tucker-Burden, D.J. Brat, X. Kong, W. Meng, Z. Zhou, Y. Li, B. Zhou, R. Wang, L. Zhan, L. Yang, W. Yu, Q. Wu, J. Lian, F. Li, S. Liu, A. Li, Z. He, K. Shao, W. Pu, J. Zhang, S. Guo, F. Qian, I. Glurich, Q. Jin, Y. Ma, S. Ju, Z. Zhang, X. Tang, Y. Liang, G. Sun, Q. He, H. Qu, P. Gao, Y. Shu, H. Bao, S. Han, Z. Liu, N. Zhao, W. Yuan, C. Jian, X. Shu, J. Pang, L. Wang, Q. Dong, D. Jin, I.C. Salaroglio, D.C. Belisario, M. Akman, S. La Vecchia, M. Godel, D.P. Anobile, G. Ortone, S. Digiovanni, S. Fontana, C. Costamagna, K. Okazaki, H. Anzawa, N. Ota, H. Kitamura, Y. Onodera, M.M. Alam, D. Matsumaru, T. Suzuki, F. Katsuoka, K. Kinoshita, H. Sekine, H. Motohashi, M. Liu, R. Li, T. Liu, D. Zhang, M. Shen, X. Ren, Q. Sun, B.A. Sterken, T. Ackermann, C. Muller, H.R. Zuidhof, G. Kortman, A. Hernandez-Segura, M. Broekhuis, D. Spierings, V. Guryev, C.F. Calkhoven, X.Z. Liu, A. Rulina, M.H. Choi, L. Pedersen, J. Lepland, S.T. Takle, N. Madeleine, S.D. Peters, C.E. Wogsland, S.M. Grondal, D. Xia, H. Cao, C. Wu, Z. Sun, H. Liu, L.L. Lee, S.J. Kim, Y.I. Hahn, J.H. Jang, S. Saeidi, Y.J. Surh, H. Wu, J. Gu, W. Cheng, Y. Wang, Q. Wang, R. Zhang, X. Li, H. Zhang, H. Xu, F. Wang, L. Tang, K. Ning, N. Geng, F. Liu, D. Mendoza-Villanueva, S. Sharan, G.H. Summers, L.E. Dobrolecki, M.T. Lewis, J. Cao, S. Ben-Shmuel, R. Rashed, R. Rostoker, E. Isakov, Z. Shen-Orr, D. Leroith, E. Kurzejamska, J. Johansson, K. Jirstrom, V. Prakash, S. Ananthaseshan, L. Boon, J. Fuxe, P. Religa, B.H. Park, S. Kook, S. Lee, J.H. Jeong, A. Brufsky, B.C. Lee, A. Chen, J. Lu, D. Liu, X.X. Zhang, M.C. Li, C.H. Cao, D.Y. Wan, B.X. Xi, J.H. Tan, Z.Y. Yang, X.X. Feng, J. Tan, X. Zheng, M. Li, F. Ye, C. Song, C. Xu, W. Li, S. Zeng, S. Yang, R. Cheng, B. Pang, P. Sun, T.C. Hour, Y.L. Lai, C.I. Kuan, C.K. Chou, H.Y. Tu, H.T. Hu, C.S. Lin, W.J. Wu, Y.S. Pu, B. Jin, Y. Gong, L. Jiao, D. Xin, L. Zhou, Y. Jin, J. Zhou, H. Tian, X. Zhi, Z. Xiao, T. Chen, H. Yuan, Q. Chen, M. Chen, J. Yang, G. Regalo, P. Canedo, G. Suriano, C. Resende, M.L. Campos, M.J. Oliveira, C. Figueiredo, P. Rodrigues-Pereira, N. Blin, R. Seruca, S. Du, Z. Yang, X. Lu, S. Yousuf, M. Zhao, J. Miao, H. Yu, X. Zhu, M.H. Kim, A.Z. Minton, V. Agrawal, D.J. Barakat, J. Mendonca, T. Barberi, S.K. Kachhap, I. Paz-Priel, A.D. Friedman, S.R. Denmeade, D. Li, S. Huang, X. Bi, X. Pu, H. 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Stephens, J.M. Adams, S. Cory, C.T. Ishida, Y. Zhang, M.E. Halatsch, M.A. Westhoff, D. Kaloni, S.T. Diepstraten, A. Strasser, G.L. Kelly, M.A. Anderson, P.E. Czabotar, G. Lessene, A.L. Koessinger, C. Cloix, D. Koessinger, D.H. Heiland, F.J. Bock, K. Strathdee, K. Kinch, L. Martinez-Escardo, N.R. Paul, C. Nixon, W. He, M. Morsch, M. Ismail, F.U. Rehman, M. Zheng, R. Chung, M.D. Wendt, S.H.M. Wong, W.Y. Kong, C.M. Fang, H.S. Loh, L.H. Chuah, S. Abdullah, S.C. Ngai, X. Zhai, P. Liang, H. Cui, S. Ishihara, M. Yasuda, A. Ishizu, M. Ishikawa, H. Shirato, H. Haga, S. Banerjee, N. Aykin-Burns, K.J. Krager, S.K. Shah, S.B. Melnyk, M. Hauer-Jensen, S.A. Pawar, D.Y. Zhang, C. Dmello, L. Chen, V.A. Arrieta, E. Gonzalez-Buendia, J.R. Kane, L.P. Magnusson, A. Baran, C.D. James, C. Horbinski, I. Ullah, K. Chung, S. Bae, C. Kim, B. Choi, H.Y. Nam, C.O. Yun, K.Y. Lee, P. Weyerhauser, S.R. Kantelhardt, E.L. Kim, N.J. Caron, S.P. Quenneville, J.P. Tremblay, S.Y. Van Der Zanden, X. Qiao, J. Neefjes, V. Aragon-Sanabria, A. Aditya, F. Chen, B. Yoo, T. Cao, B. Madajewski, R. Lee, M.Z. Turker, K. Ma, F. Iwamoto, V. Gondi, N. Butowski, G. Falchook, A. Williams, K. Peters, J. Evans, N. Lakhani, M. McKean, S. Symeonides, J. Dauparas, I. Anishchenko, N. Bennett, H. Bai, R.J. Ragotte, L.F. Milles, B.I.M. Wicky, A. Courbet, R.J. de Haas, N. Bethel, L. Chang, A. Mondal, A. Perez, R.A. Bottens, T. Yamada, A. Shoari, R. Tooyserkani, M. Tahmasebi, D. Lowik Show less

Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we re Show more

Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides (CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo, and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known mechanisms by which the peptides act and how these have been exploited in rationally designed combination therapies. We additionally discuss lacunae in our knowledge about the peptides that merit further research. Finally, we suggest both short- and long-term directions for creating new generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating brain and other malignancies. Show less

📄 PDF DOI: 10.3390/cells12040581

amino-acid review

Computational analyses of mechanism of action (MoA): data, methods and integration †

S. Trapotsi, G. Drakakis, A. Koutsoukas +1688 more · 2022 · RSC Chemical Biology · Royal Society of Chemistry · added 2026-04-20

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Mäkelä, T. Aittokallio, M. Iwata, R. Sawada, H. Iwata, M. Kotera, Y. Yamanishi, E. Dazert, M. Colombi, T. Boldanova, S. Moes, D. Adametz, L. Quagliata, V. Roth, L. Terracciano, M. H. Heim, P. Jenoe, M. N. Hall, D. Carrella, F. Napolitano, R. Rispoli, M. Miglietta, A. Carissimo, L. Cutillo, F. Sirci, F. Gregoretti, D. Di Bernardo, A. Conesa, S. Beck Show less

The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potenti Show more

The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potential side-effects. Bioinformatic approaches, advances in machine learning techniques and the increasing deposition of high-throughput data in public databases have significantly contributed to recent advances in the field, but it is not straightforward to decide which data and methods are most suitable to use in a given case. In this review, we focus on these methods and data and their applications in generating MoA hypotheses for subsequent experimental validation. We discuss compound-specific data such as -omics, cell morphology and bioactivity data, as well as commonly used supplementary prior knowledge such as network and pathway data, and provide information on databases where this data can be accessed. In terms of methodologies, we discuss both well-established methods (connectivity mapping, pathway enrichment) as well as more developing methods (neural networks and multi-omics integration). Finally, we review case studies where the MoA of a compound was successfully suggested from computational analysis by incorporating multiple data modalities and/or methodologies. Our aim for this review is to provide researchers with insights into the benefits and drawbacks of both the data and methods in terms of level of understanding, biases and interpretation – and to highlight future avenues of investigation which we foresee will improve the field of MoA elucidation, including greater public access to -omics data and methodologies which are capable of data integration. Show less

📄 PDF DOI: 10.1039/d1cb00069a

ML review

Three human RNA polymerases interact with TFIIH via a common RPB6 subunit

K.M. Okuda, L.S. Churchman, R.D. Chapman +252 more · 2022 · Nucleic acids research · Oxford University Press · added 2026-04-20

K.M. Okuda, L.S. Churchman, R.D. Chapman, M. Heidemann, C. Hintermair, D. Eick, E. Compe, J.M. Egly, P. Di Lello, L.M. Miller Jenkins, C. Mas, C. Langlois, E. Malitskaya, A. Fradet-Turcotte, J. Archambault, P. Legault, J.G. Omichinski, M. Okuda, A. Tanaka, M. Satoh, S. Mizuta, M. Takazawa, Y. Ohkuma, Y. Nishimura, L.M. Jenkins, T.N. Jones, B.D. Nguyen, T. Hara, H. Yamaguchi, J.D. Dikeakos, E. Appella, M. Lussier-Price, S. Soni, T. Morse, G. Arseneault, J. Lafrance-Vanasse, J.J. Bieker, K. Araki, K. Ohtani, K. Potempa, M.S. Kobor, P.R. Chabot, L. Raiola, L. Cappadocia, M. Kinoshita, E. Kakumu, K. Sugasawa, Y. Nakazawa, C. Guo, T. Ogi, V. Gervais, V. Lamour, A. Jawhari, F. Frindel, E. Wasielewski, S. Dubaele, J.C. Thierry, B. Kieffer, A. Poterszman, H.T. Chen, Y. He, C. Yan, J. Fang, C. Inouye, R. Tjian, I. Ivanov, E. Nogales, B.J. Greber, T.H.D. Nguyen, P.V. Afonine, P.D. Adams, D.B. Toso, J. Cavanagh, W.J. Fairbroher, A.G., III Palmer, N.J. Skelton, F. Delaglio, S. Grzesiek, G.W. Vuister, G. Zhu, J. Pfeifer, A. Bax, B.A. Johnson, R.A. Blevins, G. Cornilescu, A.T. Brünger, C.D. Schwieters, J.J. Kuszewski, N. Tjandra, G.M. Clore, J.P. Linge, M.A. Williams, C.A. Spronk, A.M. Bonvin, M. Nilges, R.A. Laskowski, J.A.C. Rullmann, M.W. MacArthur, R. Kaptein, J.M. Thornton, R. Koradi, M. Billeter, K. Wüthrich, T. Ekimoto, J. Kurita, M. Ikeguchi, S. Yamashita, A.R. Lehmann, C. McQuin, A. Goodman, V. Chernyshev, L. Kamentsky, B.A. Cimini, K.W. Karhohs, M. Doan, L. Ding, S.M. Rafelski, D. Thirstrup, P. Cramer, D.A. Bushnell, J. Fu, A.L. Gnatt, B. Maier-Davis, N.E. Thompson, R.R. Burgess, A.M. Edwards, P.R. David, R.D. Kornberg, F. del Río-Portilla, A. Gaskell, D. Gilbert, J.A. Ladias, G. Wagner, K. Kayukawa, Y. Makino, S. Yogosawa, T. Tamura, G.L. Christensen, C.D. Kelstrup, C. Lyngsø, U. Sarwar, R. Bøgebo, S.P. Sheikh, S. Gammeltoft, J.V. Olsen, J.L. Hansen, T. Dodd, J.A. Tainer, S.E. Tsutakawa, S.M. Vos, L. Farnung, M. Boehning, C. Wigge, A. Linden, H. Urlaub, E. Evans, J. Fellows, A. Coffer, R.D. Wood, A. Tapias, J. Auriol, D. Forget, J.H. Enzlin, O.D. Schärer, F. Coin, B. Coulombe, W.L. de Laat, N.G. Jaspers, J.H. Hoeijmakers, H. Spåhr, G. Calero, L. Minakhin, S. Bhagat, A. Brunning, E.A. Campbell, S.A. Darst, R.H. Ebright, K. Severinov, S. Nouraini, J.D. Friesen, D. Xu, S. Nelson, M. Lee, A. Ishiguro, Y. Nogi, K. Hisatake, M. Muramatsu, A. Ishihama, Q. Tan, M.H. Prysak, N.A. Woychik, J.F. Briand, F. Navarro, P. Rematier, C. Boschiero, S. Labarre, M. Werner, G.V. Shpakovski, P. Thuriaux, A.I. Garrido-Godino, M.C. García-López, V. Goler-Baron, M. Selitrennik, O. Barkai, G. Haimovich, R. Lotan, M. Choder, Z.R. Qiu, B. Schwer, S. Shuman, L. Daniel, E. Cerutti, L.M. Donnio, J. Nonnekens, C. Carrat, S. Zahova, P.O. Mari, G. Giglia-Mari, Y. Yang, J. Hu, C.P. Selby, W. Li, A. Yimit, Y. Jiang, A. Sancar, Y. van der Weegen, H. Golan-Berman, T.E.T. Mevissen, K. Apelt, R. González-Prieto, J. Goedhart, E.E. Heilbrun, A.C.O. Vertegaal, D. van den Heuvel, J.C. Walter, Y. Hara, Y. Oka, O. Komine, Y. Daigaku, M. Isono, M. Shimada, N. Deger, L.A. Lindsey-Boltz, C. Engel, S. Sainsbury, A.C. Cheung, D. Kostrewa, N.A. Hoffmann, A.J. Jakobi, M. Moreno-Morcillo, S. Glatt, J. Kosinski, W.J.H. Hagen, C. Sachse, C.W. Müller Show less

Abstract In eukaryotes, three RNA polymerases (RNAPs) play essential roles in the synthesis of various types of RNA: namely, RNAPI for rRNA; RNAPII for mRNA and most snRNAs; and RNAPIII for tRNA and Show more

Abstract In eukaryotes, three RNA polymerases (RNAPs) play essential roles in the synthesis of various types of RNA: namely, RNAPI for rRNA; RNAPII for mRNA and most snRNAs; and RNAPIII for tRNA and other small RNAs. All three RNAPs possess a short flexible tail derived from their common subunit RPB6. However, the function of this shared N-terminal tail (NTT) is not clear. Here we show that NTT interacts with the PH domain (PH-D) of the p62 subunit of the general transcription/repair factor TFIIH, and present the structures of RPB6 unbound and bound to PH-D by nuclear magnetic resonance (NMR). Using available cryo-EM structures, we modelled the activated elongation complex of RNAPII bound to TFIIH. We also provide evidence that the recruitment of TFIIH to transcription sites through the p62–RPB6 interaction is a common mechanism for transcription-coupled nucleotide excision repair (TC-NER) of RNAPI- and RNAPII-transcribed genes. Moreover, point mutations in the RPB6 NTT cause a significant reduction in transcription of RNAPI-, RNAPII- and RNAPIII-transcribed genes. These and other results show that the p62–RPB6 interaction plays multiple roles in transcription, TC-NER, and cell proliferation, suggesting that TFIIH is engaged in all RNAP systems. Show less

📄 PDF DOI: 10.1093/nar/gkab612

NMR synthesis

Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A

T. Narayan, A. Dutta, A. Agarwal +541 more · 2022 · iScience · Elsevier · added 2026-04-20

T. Narayan, A. Dutta, A. Agarwal, R.J. MacKenzie, R. Pippa, C.A. Eide, J. Oddo, J.W. Tyner, R. Sears, M.P. Vitek, M.D. Odero, D.J. Christensen, B.J. Druker, A. Ashkenazi, R.C. Pai, S. Fong, S. Leung, D.A. Lawrence, S.A. Marsters, C. Blackie, L. Chang, A.E. McMurtrey, A. Hebert, A. Bene, T.C. Chambers, I. Beuvink, A. Boulay, S. Fumagalli, F. Zilbermann, S. Ruetz, T. O'Reilly, F. Natt, J. Hall, H.A. Lane, G. Thomas, M. Bhat, N. Robichaud, L. Hulea, N. Sonenberg, J. Pelletier, I. Topisirovic, R. Briffa, S.P. Langdon, G. Grech, D.J. Harrison, B.A. Carneiro, W.S. El-Deiry, T.C. Chou, A.E. Collier, D.F. Spandau, R.C. Wek, I. Cristobal, R. Manso, R. Rincón, C. Caramés, C. Senin, A. Borrero, J. Martínez-Useros, M. Rodriguez, S. Zazo, O. Aguilera, R. Rincon, C. Carames, J. Madoz-Gurpide, F. Rojo, J. Garcia-Foncillas, R.M. De Palma, S.R. Parnham, Y. Li, J.J. Oaks, Y.K. Peterson, Z.M. Szulc, B.M. Roth, Y. Xing, B. Ogretmen, D. Deng, K. Shah, M.J. Fournier, L. Coudert, S. Mellaoui, P. Adjibade, C. Gareau, M.F. Côté, R.C. Gaudreault, R. Mazroui, A.M. Gaben, C. Saucier, M. Bedin, V. Barbu, J. Mester, C. Filion, D. Martel, Y. Labelle, A.G. Georgakilas, O.A. Martin, W.M. Bonner, M.J. Gerdes, C.J. Sevinsky, A. Sood, S. Adak, M.O. Bello, A. Bordwell, A. Can, A. Corwin, S. Dinn, R.J. Filkins, M. Gorospe, X. Wang, K.Z. Guyton, N.J. Holbrook, M.M. Gottesman, J.R. Graff, B.W. Konicek, J.H. Carter, E.G. Marcusson, R.S. Herbst, S.G. Eckhardt, R. Kurzrock, S. Ebbinghaus, P.J. O'Dwyer, M.S. Gordon, W. Novotny, M.A. Goldwasser, T.M. Tohnya, B.L. Lum, S.D. Heys, K.G. Park, M.A. McNurlan, A.G. Calder, V. Buchan, K. Blessing, O. Eremin, P.J. Garlick, B. Hoang, A. Benavides, Y. Shi, Y. Yang, P. Frost, J. Gera, A. Lichtenstein, A.N. Hobden, E. Cundliffe, N. Ikoma, K. Raghav, G. Chang, A. Ishitsuka, E. Fujine, Y. Mizutani, C. Tawada, H. Kanoh, Y. Banno, M. Seishima, S. Iwasaki, N.T. Ingolia, S.C. Jahn, P.E. Corsino, B.J. Davis, M.E. Law, P. Nørgaard, B.K. Law, V. Janssens, S. Longin, J. Goris, M.A. Jensen, V. Ferretti, R.L. Grossman, L.M. Staudt, Y.H. Jin, K.J. Yoo, Y.H. Lee, S.K. Lee, A. Kahvejian, Y.V. Svitkin, R. Sukarieh, M.N. M'Boutchou, S.K. Kelley, L.A. Harris, D. Xie, L. Deforge, K. Totpal, J. Bussiere, J.A. Fox, S.L. Kim, Y.C. Liu, Y.R. Park, S.Y. Seo, S.H. Kim, I.H. Kim, S.O. Lee, S.T. Lee, D.G. Kim, S.W. Kim, N.N. Kreis, F. Louwen, J. Yuan, M. Law, E. Forrester, A. Chytil, P. Corsino, G. Green, B. Davis, T. Rowe, B. Law, S.L. Lehman, G.J. Cerniglia, G.J. Johannes, J. Ye, S. Ryeom, C. Koumenis, S. Lek, J. Vargas-Medrano, E. Villanueva, B. Marcus, W. Godfrey, R.G. Perez, J. Lemke, S. von Karstedt, J. Zinngrebe, H. Walczak, D. Leonard, W. Huang, S. Izadmehr, C.M. O'Connor, D.D. Wiredja, Z. Wang, N. Zaware, Y. Chen, D.M. Schlatzer, J. Kiselar, V. Leung-Pineda, C.E. Ryan, H. Piwnica-Worms, L. Li, J. Wang, J.G. Li, Z. Wu, P. Ma, X.J. Lian, I.E. Gallouzi, H. Lin, X. Qiu, B. Zhang, J. Zhang, T.A. Lin, X. Kong, T.A.J. Haystead, A. Pause, G. Belsham, J.C. Lawrence, J. Lu, J.S. Kovach, F. Johnson, J. Chiang, R. Hodes, R. Lonser, Z. Zhuang, M. Mahyar-Roemer, K. Roemer, A. Maiuthed, C. Ninsontia, K. Erlenbach-Wuensch, B. Ndreshkjana, J.K. Muenzner, A. Caliskan, H. Ahmed P, A.P. Husayn, C. Chaotham, A. Hartmann, K. Malinowsky, U. Nitsche, K.P. Janssen, F.G. Bader, C. Spath, E. Drecoll, G. Keller, H. Hofler, S. Mazhar, S.E. Taylor, J. Sangodkar, G. Narla, K. McClinch, R.A. Avelar, D. Callejas, D. Wiredja, A. Perl, D.B. Kastrinsky, D. Schlatzer, M. Cooper, D.R. McIlwain, T. Berger, T.W. Mak, N. Melling, R. Simon, J.R. Izbicki, L.M. Terracciano, C. Bokemeyer, G. Sauter, A.H. Marx, J.R. Mills, Y. Hippo, F. Robert, S.M.H. Chen, A. Malina, C.J. Lin, U. Trojahn, H.G. Wendel, A. Charest, R.T. Bronson, C.S. Mitsiades, S.P. Treon, N. Mitsiades, Y. Shima, P. Richardson, R. Schlossman, T. Hideshima, K.C. Anderson, K. Morita, S. He, R.P. Nowak, M.W. Zimmerman, C. Fu, A.D. Durbin, M.W. Martel, N. Prutsch, N.S. Gray, S. Narayan, A.S. Jaiswal, R. Sharma, A. Nawab, L.V. Duckworth, M. Zajac-Kaye, T.J. George, J. Sharma, A.K. Sharma, R.A. Hromas, S. Ramisetti, A. Singh-Pillay, P. Singh, S. Amin, P. Palaiologos, D. Chrysikos, S. Theocharis, G. Kouraklis, G.J. Belsham, A.C. Gingras, O. Donzé, M.D. Ralff, P.G. Richardson, C. Eng, J. Kolesar, N.R. Rodrigues, A. Rowan, M.E. Smith, I.B. Kerr, W.F. Bodmer, J.V. Gannon, D.P. Lane, H.K. Roy, B.F. Olusola, D.L. Clemens, W.J. Karolski, A. Ratashak, H.T. Lynch, T.C. Smyrk, E. Rozengurt, H.P. Soares, J. Sinnet-Smith, P.P. Ruvolo, R. Tohme, E.K. Schmidt, G. Clavarino, M. Ceppi, P. Pierre, R.R. Sharma, T.S. Ravikumar, D. Raimo, W.L. Yang, R.L. Siegel, K.D. Miller, H.E. Fuchs, A. Jemal, J.C. Soria, Z. Márk, P. Zatloukal, B. Szima, I. Albert, E. Juhász, J.L. Pujol, J. Kozielski, N. Baker, D. Smethurst, W. Stöcklein, W. Piepersberg, A. Surov, P. Clauser, Y.W. Chang, L. Martincich, S.C. Partridge, J.Y. Kim, H.J. Meyer, A. Wienke, A. Suzuki, T. Ito, H. Kawano, M. Hayashida, Y. Hayasaki, Y. Tsutomi, K. Akahane, T. Nakano, M. Miura, K. Shiraki, T. Araki, S. Tahmasebi, T. Alain, V.K. Rajasekhar, J.P. Zhang, M. Prager-Khoutorsky, A. Khoutorsky, Y. Dogan, C.G. Gkogkas, E. Petroulakis, A. Sylvestre, A. Thorburn, K. Behbakht, H. Ford, H. Tian, E.K. Wittmack, T.J. Jorgensen, R. Tohmé, S. Gandhe, G. Tabaro, S. Vallabhaneni, A. Thomas, N. Vasireddi, N.S. Dhawan, A. Ma'ayan, N. Sharma, C. Vaklavas, S.W. Blume, W.E. Grizzle, K. Van der Jeught, H.C. Xu, Y.J. Li, X.B. Lu, G. Ji, A. Montinaro, R.E. Miller, K. Ariail, B. Gliniak, T.S. Griffith, M. Kubin, W. Chin, J. Jones, A. Woodward, T. Le, H. Wang, Y. Liu, J. Ding, Y. Huang, J. Liu, N. Liu, Y. Ao, Y. Hong, L. Wang, L. Zhang, M. Wang, E. Yaaghubi, A.F. Ghilardi, R.B. Ferreira, C.W. Chiang, O.A. Guryanova, D. Kopinke, C.D. Heldermon, S.S. Wang, E.D. Esplin, J.L. Li, L. Huang, A. Gazdar, J. Minna, G.A. Evans, X.W. Wang, Y.J. Zhang, J.S. Warmus, G.J. Dilley, A.I. Meyers, F. Wei, Y. Zhang, L. Geng, P. Zhang, G. Wang, R.H. Weiss, J. Westermarck, N. Wu, Z. Du, Y. Zhu, Y. Song, L. Pang, Z. Chen, J. Xu, P. Wang, H. Yang, J. Zhou, X. Li, W. Xue, C. Yu, Y. Tian, F. Zhu, J.Y. Zhou, W.Z. Wei, G.S. Wu, S.Q. Xu, P. Yaffee, A. Osipov, C. Tan, R. Tuli, A. Hendifar, L. Yong, Z. YuFeng, B. Guang, P.E. Young, C.M. Womeldorph, E.K. Johnson, J.A. Maykel, B. Brucher, A. Stojadinovic, I. Avital, A. Nissan, S.R. Steele, Y. Yu, S.S. Kanwar, B.B. Patel, J. Nautiyal, F.H. Sarkar, A.P. Majumdar, B. Fang, N. Fujita, T. Tsuruo, X. Zhou, W. Liu, X. Hu, A. Dorrance, R. Garzon, P.J. Houghton, C. Shen Show less

Summary The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTO Show more

Summary The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTOR/4EBP1 and levels of p21 in FOLFOX-resistant CRC cells. We have identified a small molecule, NSC49L, that stimulates protein phosphatase 2A (PP2A) activity, downregulates the AKT1/mTOR/4EBP1-axis, and inhibits p21 translation. We have provided evidence that NSC49L- and TRAIL-mediated sensitization is synergistically induced in p21-knockdown CRC cells, which is reversed in p21-overexpressing cells. p21 binds with procaspase 3 and prevents the activation of caspase 3. We have shown that TRAIL induces apoptosis through the activation of caspase 3 by NSC49L-mediated downregulation of p21 translation, and thereby cleavage of procaspase 3 into caspase 3. NSC49L does not affect global protein synthesis. These studies provide a mechanistic understanding of NSC49L as a PP2A agonist, and how its combination with TRAIL sensitizes FOLFOX-resistant CRC cells. Show less

📄 PDF DOI: 10.1016/j.isci.2022.104518

amino-acid synthesis

Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox Signaling Reviewing Editors: Jerzy Beltowski, Joseph Burgoyne, Gabor Csanyi, Sergey Dikalov, Frank Krause, Anibal Vercesi, and Jeremy Ward

JP Ježek, AGW Leslie, R Lutter +1993 more · 2018 · Antioxidants & redox signaling · added 2026-04-20

JP Ježek, AGW Leslie, R Lutter, JE Walker, AE Adams, AM Carroll, PG Fallon, RK Porter, O Hanrahan, DN Nolan, HP Voorheis, P Fallon, OM Kelly, C Affourtit, MD Brand, M Jastroch, C Aguer, BD Piccolo, O Fiehn, SH Adams, ME Harper, L Alán, K Smolková, E Kronusová, J Šantorová, P Ježek, EM Allister, CA Robson-Doucette, KJ Prentice, AB Hardy, S Sultan, HY Gaisano, D Kong, P Gilon, PL Herrera, BB Lowell, MB Wheeler, R Amat, G Solanes, M Giralt, F Villarroya, ZB Andrews, ZW Liu, N Walllingford, DM Erion, E Borok, JM Friedman, MH Tschöp, M Shanabrough, G Cline, GI Shulman, A Coppola, XB Gao, TL Horvath, S Diano, MA Aon, S Cortassa, E Marbán, B O'Rourke, H Aquila, TA Link, M Klingenberg, D Arsenijevic, H Onuma, C Pecqueur, S Raimbault, BS Manning, B Miroux, E Couplan, MC Alves-Guerra, M Goubern, R Surwit, F Bouillaud, D Richard, S Collins, D Ricquier, V Ayyasamy, KM Owens, MM Desouki, P Liang, A Bakin, K Thangaraj, DJ Buchsbaum, AF LoBuglio, KK Singh, V Azzu, EP Breen, N Parker, G Baffy, Z Derdak, SC Robson, Y Bai, X Bai, AV Medvedev, M Misukonis, JB Weinberg, W Cao, J Robidoux, LM Floering, KW Daniel, KA Ball, AW Nelson, DG Foster, RO Poyton, J Barlow, V Hirschberg Jensen, CJ Barnstable, R Reddy, H Li, W Basu Ball, S Kar, M Mukherjee, AG Chande, R Mukhopadhyaya, PK Das, JM Baughman, F Perocchi, HS Girgis, M Plovanich, CA Belcher-Timme, Y Sancak, XR Bao, L Strittmatter, O Goldberger, RL Bogorad, V Koteliansky, VK Mootha, V Beck, M Jabůrek, EE Pohl, T Demina, A Rupprecht, EL Bell, TA Klimova, J Eisenbart, CT Moraes, MP Murphy, GRS Budinger, NS Chandel, MJ Berardi, JJ Chou, WM Shih, SC Harrison, M Bertolotti, G Farinelli, M Galli, A Aiuti, R Sitia, J Blanc, B Esposito, S Rousset, P Gourdy, A Tedgui, Z Mallat, L Bleier, S Dröse, M Board, C Lopez, C van den Bos, R Callaghan, K Clarke, C Carr, AI Bondarenko, W Parichatikanond, CT Madreiter, R Rost, M Waldeck-Weiermair, R Malli, WF Graier, J Borecký, D Siemen, O Boss, S Samec, A Paoloni-Giacobino, C Rossier, A Dulloo, J Seydoux, P Muzzin, JP Giacobino, S Boudina, S Sena, BT O'Neill, P Tathireddy, ME Young, ED Abel, H Theobald, X Sheng, JJ Wright, XH Xia, S Aziz, JI Johnson, H Bugger, VG Zaha, TC Esteves, J Brandi, D Cecconi, M Cordani, M Torrens-Mas, R Pacchiana, E Dalla Pozza, G Butera, M Manfredi, E Marengo, J Oliver, P Roca, I Dando, M Donadelli, MO Breckwoldt, FMJ Pfister, PM Bradley, P Marinković, PR Williams, MS Brill, B Plomer, A Schmalz, DK St Clair, R Naumann, O Griesbeck, M Schwarzländer, L Godinho, FM Bareyre, TP Dick, M Kerschensteiner, T Misgeld, W Pilgrim, KJ Clarke, C Yssel, M Farrell, J Zhou, PV Murphy, PS Brookes, JA Buckingham, A Vidal-Puig, AP Halestrap, TE Gunter, DG Nicholls, P Bernardi, JJ Lemasters, A Bugge, M Siersbæk, MS Madsen, A Göndör, C Rougier, S Mandrup, C Guzman, C Zechner, M Palmeri, KS Russell, RR Russell, JA Cabrera, EA Ziemba, R Colbert, RF Kelly, M Kuskowski, EA Arriaga, W Sluiter, DJ Duncker, HB Ward, EO McFalls, V Calegari, CC Zoppi, L Rezende, L Silveira, E Carneiro, AC Boschero, B Cannon, IG Shabalina, TV Kramarova, N Petrovic, J Nedergaard, A Caron, SM Labbé, S Carter, MC Roy, R Lecomte, F Picard, LR Haines, TW Pearson, CM Walsh, CM Brennan, E Casanova, L Baselga-Escudero, A Ribas-Latre, A Arola-Arnal, C Bladé, L Arola, MJ Salvadó, HZ Chae, H Oubrahim, JW Park, SG Rhee, PB Chock, CB Chan, SL Chan, D Liu, GA Kyriazis, P Bagsiyao, X Ouyang, MP Mattson, L Chaudhuri, RK Srivastava, F Kos, PA Shrikant, M Che, R Wang, X Li, HY Wang, XFS Zheng, C Chen, K Wang, J Chen, J Guo, Y Yin, X Cai, X Guo, G Wang, R Yang, L Zhu, Y Zhang, J Wang, Y Xiang, C Weng, K Zen, J Zhang, CY Zhang, Y Chen, J Liu, Y Zheng, Z Wang, S Gu, J Tan, Q Jing, H Yang, J Cheng, G Nanayakkara, Y Shao, R Cueto, L Wang, WY Yang, Y Tian, H Wang, X Yang, N Cheurfa, D Dubois-Laforgue, DAF Ferrarezi, AF Reis, GM Brenner, C Bouche, C Le Feuvre, F Fumeron, J Timsit, M Marre, G Velho, SY Cho, D Seo, WG Kim, S Lee, YS Cho, JH Lee, KH Jung, SH Moon, YS Choe, KH Lee, ET Chouchani, L 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Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology Show more

Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δ p or its potential component, Δ Ψ , which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1–5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δ p dissipation decreases superoxide formation dependent on Δ p . UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. Critical Issues: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg 2+ , or increased pyruvate accumulation may initiate UCP-mediated redox signaling. Future Directions: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667–714. Show less

📄 PDF DOI: 10.1089/ars.2017.7225